Pharmacokinetics and Pharmacodynamics of NPH Insulin in Type 1 Diabetes: The Importance of Appropriate Resuspension Before Subcutaneous Injection

Abstract

OBJECTIVECrystalline NPH insulin comes in a two-phase solution with either a solvent or a rapid-acting insulin (in premixed formulations) and needs adequate mixing for complete resuspension before injection. The aim of this study was to establish pharmacokinetics (PK) and pharmacodynamics (PD) after injection of appropriately resuspended versus nonresuspended NPH insulin. RESEARCH DESIGN AND METHODSPK and PD were assessed after subcutaneous injection of NPH insulin 0.35 units/kg at steady state by pen either resuspended (R+, tipping of insulin pen 20 times) or nonresuspended (pen maintained in fixed position either horizontally [R-horizontal] or vertically with tip up [R-up] or tip down [R-down]). Eleven subjects with type 1 diabetes (age 31.5 6 12 years, diabetes duration 17.5 6 7.7 years, BMI 22.9 6 1.5 kg/m 2 , A1C 7.2 6 0.4% [55.2 6 4.4 mmol/mol]) were studied (euglycemic clamp) with a randomized crossover design. RESULTSCompared with resuspended NPH insulin (R+), nonresuspended NPH insulin resulted in profound PK/PD differences with either reduced (R-horizontal and R-up) or increased (R-down) plasma insulin concentrations [FIRI_AUC (0-end of study) (free immunoreactive insulin area under the concentration-time curve between 0 and end of study)] and PD activity [glucose infusion rate (GIR)_AUC (0-end of study) ] (all P < 0.05). Duration of NPH insulin action was shorter in R-up (9.4 6 1.7 h) but longer in R-down (15.4 6 2.3 h) compared with R+ (11.8 6 2.6 h) (P < 0.05). Within-subject variability (percent coefficient of variation) among studies was as high as 23% for PK [FIRI_AUC (0-end of study) ] and 62% for PD [GIR_AUC (0-end of study) ]. CONCLUSIONSCompared with resuspended NPH insulin, lack of resuspension profoundly alters PK/PD and may importantly contribute to day-to-day glycemic variability of type 1 diabetes.

Evaluation of a Premixed Insulin Analog Suspension in Japanese People with Type 2 Diabetes and the Clinical Importance of Improved Injection Techniques: A Cross-Sectional Pilot Study

“…Similar to previously reported findings [3–5], the current results suggest that it is important to resuspend premixed insulin analogs, especially high-mix biphasic insulin analogs, more carefully before injection. …”

“…Protaminated insulin aspart and lispro are cloudy, and the degree of cloudiness should correspond to the ratio of rapid-acting insulin in a prefilled pen. Therefore, insulin cartridges and pens prefilled with insulin–protamine complex in binding mode will require adequate mixing to ensure a complete resuspension [3, 4]. Insufficient mixing will cause patients to receive inaccurate doses of intermediate- and/or short-acting insulin, which could significantly affect diabetes control.…”

ISPAD Clinical Practice Consensus Guidelines 2018: Insulin treatment in children and adolescents with diabetes

“…As they are in suspension adequate preinjection mixing has to be ensured. In one study, the insulin concentration in used vials and cartridges of NPH insulin that had not been mixed thoroughly varied between 5 and 200 U/mL . Nevertheless, they are associated with greater inter‐ and intraindividual variability compared to soluble basal insulins and the peak effect makes them less functional when carbohydrate counting is practiced.…”

In response to: Heise T, Nørskov M, Nosek L, Kaplan K, Famulla S and Haahr H. L. (2017) Insulin degludec: Lower day‐to‐day and within‐day variability in pharmacodynamic response compared to insulin glargine U300 in type 1 diabetes. Diabetes Obes Metab. 2017;19:1032–1039

“…Upon injection these crystals are sieved by the tissue and form clusters. As a result, depending on pre‐injection preparation, and the size and shape of individual crystals and clusters, there is variability in absorption …”

“…As a result, depending on pre-injection preparation, and the size and shape of individual crystals and clusters, there is variability in absorption. 26,27 By contrast, soluble insulin products such as IGlar300 can be injected without such preparations. IGlar is released from amorphous precipitates formed during injection into subcutaneous tissue as the result of the pH-dependent change in solubility.…”